Differentiating HCL-v from HCL has significant treatment implications in the setting of relapsed or refractory disease. HCL is typically treated with purine analogues, in particular cladribine or pentostatin, with moderate success. In a 2020 analysis of 208 patients treated for HCL with either cladribine or pentostatin, the complete response rates were 83% and 84%, respectively. In other cases, treatment with recombinant interferon–alpha A or the more recent BRAF inhibitors (vemurafenib), Bruton's tyrosine kinase pathway inhibitors (ibrutinib), MEK inhibitors (trametinib), and anti-CD20 monoclonal antibodies (rituximab) has also shown success.[19,20] In comparison, treatment with cladribine or pentostatin is less effective for HCL-v, with estimated respective overall response rates of 48% and 55%. Nevertheless, these treatments, along with rituximab, are still considered first-line chemotherapy for patients with HCL-v.
Historically, splenectomy has been an aspect of HCL treatment used in combination with chemotherapy, although with the development of more targeted therapy, this procedure is becoming less utilized. Still, splenectomy has been shown to be a viable option for patients with HCL-v in past reports. More recently, moxetumomab pasudotox, a recombinant anti-CD22 immunotoxin, has received approval from the US Food and Drug Administration for use in relapsed or refractory HCL and has shown a high rate of durable response. In the present case, the patient's disease relapsed after treatment with cladribine and rituximab, eventually necessitating a trial of bendamustine and rituximab, which has been shown to be effective for relapsed or refractory HCL-v.
Gene sequencing has become a useful therapeutic tool in oncology because it enables physicians to find targetable mutations in relapsed or refractory cases. In this case, trametinib, a MEK inhibitor, was considered as a prospective treatment because of its efficacy in treating other malignancies with MAP2K1 mutations. Activating MAP2K1 mutations have been reported in 10 of 24 (42%) HCL-v cases, compared with 6 of 27 (22%) HCL cases, although more recent studies have recorded a prevalence of 7%-9% in HCL-v.[26,27] Trametinib and dabrafenib, a BRAF inhibitor, are currently approved by the FDA for the treatment of metastatic melanoma, non–small cell lung cancer, and thyroid cancer with a BRAF V600E or V600K mutation. This therapy is also showing a high rate of durable response in patients with relapsed or refractory BRAF V600E-mutated HCL in an ongoing clinical trial.
Secondary central nervous system (CNS) involvement by HCL has been described in several case reports, typically with worse outcomes.[5,28,29] No cases of secondary CNS involvement by HCL-v have previously been reported. In the present case, direct CNS involvement by HCL-v is possible but cannot be confirmed without a brain biopsy, and the HCL-v cells found in the CSF could be a secondary to hemorrhage. Brain hemorrhage can occur as a result of leukemic bone marrow suppression and secondary thrombocytopenia, although this patient's platelet counts were within normal ranges. Leukemia is also known to disrupt various hemostatic mechanisms and may cause disseminated intravascular coagulation, particularly with acute promyelocytic leukemia.
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